3-oxygenated-30-methylolean-12-en-30-ones and 11-oxo derivatives thereof

ABSTRACT

3B-ACETOXY-18B-OLEAN-12-EN-30-OIC ACID AND ITS 11-OXO DERIVATIVES ARE CONVERTED TO THE ACID CHLORIDE AND METHYLATED TO AFFORD THE 3B-ACETOXY-30-METHYL-18B-OLEAN-12-EN30-ONE AND 3B-ACETOXY-30-METHYL-18B-OLEAN-12-ENE-11,30DIONE COMPOUNDS, RESPECTIVELY. THOSE INTERMEDIATES THEN ARE TREATED WITH BASE TO PRODUCE THE 3B-HYDROXY DERIVATIVES, WHICH ARE OXIDIZED TO THE 3-OXO-DERIVATIVES. THE 3B-HYDROXY AND 3-OXO COMPOUNDS EXHIBIT VALUABLE PHARMACOLOGICAL, E.G. ANTI-INFLAMMATORY AND ANTI-HYPERTENSIVE, ACTIVITY.

United States Patent 3,810,927 S-OXYGENATED 30 METHYLOLEAN-12-EN-30- ONES AND 11-0X0 DERIVATIVES THEREOF John S. Baran, Morton Grove, and Chi-Dean Liang, Glen- ;lilew, Ill., assignors to G. D. Searle 8: Co., Chicago,

No Drawing. Filed Feb. 10, 1972, Ser. No. 225,275 Int. Cl. A611: 27/00; C07c 49/54, 49/56 U.S. Cl. 260-410 Claims ABSTRACT OF I THE DISCLOSURE 3';8-acetoxy-18fl-olean-l2-en-30-oic acid and its ll-oxo derivatives are converted to the acid chloride and methylated to aiford the 3B-acetoxy-30-methyl-18,5-olean-l2-en- 30-one and 3B acetoxy-30-methy1-18/3-olean-12-ene-11,30- dione compounds, respectively. Those intermediates then are treated with base to produce the SB-hydroxy derivatives, which are oxidized to the 3-oxo derivatives. The 3B-hy'droxy and 3-oxo compounds exhibit valuable pharmacological, e.g. anti-inflammatory and anti-hypertensive, activity.

The present invention is concerned generally with members of the oleanane family. More particularly, it is concerned with compounds of the structural formula wherein X is carbonyl or a methylene radical, Z is a carbonyl, (lower alkanol)oxymethylene, stearoyloxy-methylene or hydroxymethylene radical and the wavy line represents the alternative 1 80; or 1813 configuration. The lower alkanoyl radicals represented in the above formula contain up to 7 carbon atoms and are illustrated by acetyl and propionyl.

A preferred method of manufacturing the ll-oxo compounds and ll-desoxy compounds of this invention begins with the formation of the acid chlorides by contacting the appropriate 3-(lower alkanoyDoxy acids with thionyl chloride. In that manner, Sfi-acetoxy-l1-oxo-18/3-oleanl2-en-30-oic acid and 3fl-acetoxy-18p-olean-12-en-30-oic acid are converted to the corresponding Sfi-acetoxy-lloxo-18p-olean-12-en-30-oyl chloride and 3B-acetoxy-18fiolean-12-en-30'oyl chloride, respectively. Treatment of the acid chlorides with dimethyl cadmium affords the methylated derivatives, 3fi-acetoxy-30-methyl-18p-olean- 12-ene-11,30-dione and 3,8-acetoxy-30-methyl-18p-olean- 12-en-30-one. Hydrolysis of the S-(lower alkanoyDoxy compounds, accomplished by refluxing those compounds in base, such as an alcoholic sodium hydroxide solution, alfords the 3-hydroxy derivatives, 35-hydroxy-30-methyl- 18fl-olean-12-ene-11,30-dione and 3p-hydroxy-30-methyll8p-olean-l2-en-30-one, and oxidation of the latter compounds. with aqueous chromic acid produces the instant 3-oxo-derivatives, 30-methyl 185 olean-12-ene-3,11, 30- trione and SO-r'netliyl-1Sp-olean-12-ene-3,30-dione.

For the purposes of this invention, it is understood that the 18a-derivatives are equivalent to the corresponding lite-derivatives and may be reacted in the same manner as the IS S-compounds to produce the instant liter-products.

The compounds of this invention are useful as pharmacological agents in view of their biological, e.g. antiinfiammatory and anti-hypertensive, activity. For example, 3 8 hydroxy-30-methy1-18fl-olean-l2-ene-11,30-dione and 3fi-hydroxy-30-methyl 18;; olean-12-en-30-one are active intragastrically in the following assay which is designed to determine anti-inflammatory activity.

Intact, male Sprague-Dawley rats, weighing -200 g., are injected intradermally on the base of the tail with 0.6 mg. of dry, heat-killed Mycobacterium butyricum sus pended in 0.05 ml. of paraliin oil. The animals are randomized into groups of 12 and daily treatment with compounds is begun. Compounds are administered subcutaneously or intragastrically for 19 consecutive days. The rats are sacrificed on the 20th day and the degree of swelling in the hind paws is determined by a volume displacement apparatus or by ankle circumference measurement. Each treated group is compared statistically with the control group and the compound is rated active if it causes a significant reduction in swelling (P 0.05) as compared to the control (Wilcoxon Rank Sum).

The anti-hyptertensive activity of the instant 30-methyl-lSfi-oleam12-ene-3,30-dione is demonstrated by the following assay:

The test procedure makes use of the fact that chronic administration of desoxycorticosterone acetate induces a self sustaining hypertension that is similar in many respects to essential hypertension in man (D. N. Green et al., American Journal of Physiology, 170 94 1952). In this test, 50-g. male Charles River rats are implanted with a 20 mg. wax pellet containing 10 mg. of desoxycorticosterone acetate. After 5 weeks, their systolic blood pressures are measured electrosphygmorgraphically on the tail artery. The following day, groups of 5 rats are then given 60 mpk. of test compound intragastrically. Four hours later, the blood pressures are again measured and the decrease in pressure from control day is calculated and compared with concurrent controls. The compound is con sidered active if it produces a significant decrease in sys tolic blood pressure.

The anti-hypertensive activity of 30-methyl-l8p-olean- 12-ene-3,11,30-tri0ne is determined by an assay described in US. Pat. 3,455,921.

The invention will appear more fully from the examples which follow. They are not to be construed as limiting the invention either in spirit or in scope as many modifications in materials and methods will be apparent to those skilled in the art. Temperatures are given in degrees centigrade C.) and quantities of material in parts by weight unless parts by volume is specified.

EXAMPLE 1 the solid and the solution is brought to reflux temperature. After cooling, the solid is recovered by filtration and dried to yield 3fi-acetoxy-l l-oxo-l8B-olean-12-en-30-oyl chloride.

EXAMPLE 2 l2-en-30-oic acid is substituted in the procedure of Exam- When an equivalent quantity of 3fl-acetoxy-1818-olean! 0.25 part of magnesium turnings is covered by 36 parts of ether and 1.4 parts of methyl iodide in 7 parts of ether is added to that mixture over a 1 hour period. Then the mixture is cooled in an ice bath and 1.0 part of cadmium chloride, which was dried at 110 for 1 hour, is added over a 5 minute period. The mixture is removed from the ice bath, stirred at room temperature for 5 minutes and refluxed for 45 minutes. Then the ether is removed by distillation and 8.8 parts of anhydrous benzene is added. After cooling the mixture to room temperature, 3.0 parts of 3 3-acetoxy1l-oxo-l8,8-olean-12-en-30-oyl chloride is added and the mixture is refluxed for 2 hours. Cooling of the reaction mixture followed by the addition of ice water and 20% sulfuric acid affords two phases. The organic phase is separated, successively washed with water, aqueous sodium bicarbonate solution and water until neutral and dried over anhydrous magnesium sulfate. Then the benzene is evaporated and the material remaining is recrystallized from methanol to yield 3fi-acetoxy-30-methyl- 18fl-olean-12-ene-11,30-dione, melting at about 278279. That compound is represented by the following structural formula EXAMPLE 4 Substitution of an equivalent quantity of 3B-acetoxy- 18fl-olean-12-en-30-oyl chloride in the procedure of Example 3 yields Sfl-acetoxy-BO-methyl-l8fl-olean-12-en-30- one. That compound melts at about 232-233 and is represented by the following structural formula \icm I OH: CH:

who

cii. om

EXAMPLE A solution of 0.350 part of 3fi-acetoxy-30-methyl-18polean-12-en-30-one, 16.3 parts of denatured ethanol and 15 parts by volume of a 0.2 N potassium hydroxide in ethanol solution is refluxed for 1 hour. Then the ethanol is evaporated and the organic material is extracted with chloroform, washed with water until neutral, dried and recrystallized from ethanol to yield 3 fl-hydroxy-30-methyl- 18fi-olean-l2-en-30-one. That compound melts at about 235-237" and is represented by the following structural formula cri; cm

EXAMPLE 6 EXAMPLE 7 To a stirred solution, cooled to 0", of 0.500 part of 3B- hydroxy-30-methyl-18,3-olean-12-en-30-one dissolved in 31.5 parts of acetone is added, portionwise, 0.6 part by volume of 4 M chromic acid and 0.20 part of magnesium sulfate. The addition schedule is such that the temperature remains at less than 4. After the addition is complete, the mixture is stirred for an additional 10 minutes. Then a solution containing 3.14 parts of isopropanol, 0.5 part of potassium carbonate and 3 parts of water is added in one portion. The mixture is filtered and the filtrate is evaporated to dryness. The material remaining is recrystallized from methanol to yield 30-methyl-18fl-olean-12-ene-3,30- dione. That compound melts at about 260-264 and is represented structurally by the following formula cit,

Off; CH3

EXAMPLE 8 By substituting an equivalent quantity of 3-hydroxy-30- methyl-18p-olean-12-ene-11,30-dione in the procedure of Example 7, there is produced 30-methyl-l8p-olean42-enc- 3,11,30-trione. Recrystallization from ethyl acetate affords pure material melting at about 296-298. That compound is represented by the following structural formula EXAMPLE 9 To a solution of 0.250 part of 3fl-hydroxy-30-methyl- 18B-olean-12-en-30-one in 3 parts of pyridine is added 0.150 part of stearoyl chloride and the mixture is stirred at room temperature for 2 hours. Then an additional 0.200 part of stearoyl chloride is added and, after stirring the solution for an additional V2 hour, ether and ice water are added. The organic layer is washed with water until neutral and then dried over anhydrous sodium sulfate. The solvent is evaporated and the oily material which remains is extracted with methanol. The volume of the methanol extract is reduced to V: of its original volume by heating and the solution is cooled to room temperature. The remaining solvent is evaporated under reduced pressure to afford crude product which, when chromatographed on silica gel with ethyl acetate-benzene as eluant and recrystallized from methanol, yields pure 3pstearoyloxy-SO-methyl-l8fl-0lean-l2-en-30-one, melting at about 119-120".

'EXAMPLE 10 When an equivalent quantity of 3 3-hydroxy-30-methyL- 18/3-olean-12-ene-11,30-dione is substituted in the procedure of Example 9, there is obtained Sfl-stearoyloxy-BO- methyl-18fl-olean-l2-ene-l1,30-dione.

EXAMPLE 11 By substituting an equivalent quantity of 3fl-propionyloxy-ll-oxo-18B-olean-l2-en-30-oic acid in the procedure of Example 1 and otherwise successively following the procedures outlined in Examples 1, 3 and 6, there is produced, respectively, 3 fi'propionyloxy-l l-oxo-l8p-olean-12- en-30-oyl chloride, 3B-propionyloxy-30-methyl-ISB-olean- 12-ene-11,30-dione and 3p-hydroxy-30-methyl-18/8-olean- 12-ene-1l,30-dione. The latter compound isidentical to the product of Example 6.

EXAMPLE 12 By substituting an equivalent quantity of 3,8-propionyloxy-18/3-olean-l2-en-30-oic acid in the procedure of Example 1 and otherwise successively following the procedures of Examples 1, 3 and 5, there is obtained, respectively, 3 8-propionyloxy-18fi-olean-l2-en-30-oyl chloride, 3}? propionyloxy-30 methyl-lSB-olean-lZ-en-BO-one and 3fl-hydroxy-30-methyl-l8fl-olean-l2-en-30-one. The latter compound is identical to the product of Example 5.

What is claimed is:

1 A compound of the formula wherein X is selected from the group consisting of carbonyl and methylene radicals, Z is selected from the group consisting of carbonyl, p-(lower alkanoyl)oxymethylene, fl-stearoyloxymethylene and fl-hydroxymethylene radicals and the wavy line represents the alternative 0r 18B configuration.

2. As in claim 1, a compound of the formula wherein Z is selected from the group consisting of carbonyl, p-(lower alkanoyl)oxymethylene, p-stearoyloxymethylene and fl-hydroxymethylene radicals and the wavy line represents the alternative 180: or 18/8 configuration.

3. As in claim 1, a compound of the formula wherein Z is selected from the group consisting of carbonyl, fl-(lower aIkanoyD XymethyIene',ffi stearoylbx methylene and fl-hydroxi methylenia radicals and the wavy line represents the alternative 180: or 185 configuration.

4. As in claim 1, the compound which is 3fl-acetoxy- 30-methy1-18B-olean-l2-ene-1 1,3 O-dione.

5. As in claim 1, the compound which is 35 acetoxy- 30-methyl-18fi-olean-l2-en-30-one.

6. As in claim 1, the compound which is 3fi-hydroxy- 30-methyl-l8p-olean-l2-en-30-one.

7. As in claim 1; the compound which is Bfl-hydroxy- 30-methyl-18fl-olean 12-ene-1 1,30.-dione.

8. As in claim 1, the compound which is 30-methyl- 18fl-olean-12-ene-3,30-dione.

9. As in claim 1, the COmPOIlILld which is BO-methyl- 1 8fi-olean-l2-ene-3, 1 1,30-trioi1e.

- 10. As in claim 1, the compound which is 3fl-stearoyloXy-BO-m'ethyI-l8fl-olean-12-en-30-one.

References Cited UNITED STATES PATENTS 3,084,185 4/1963 Gottfried et al. 260-488 OTHER REFERENCES Brieskorn et al.: Archiv der Pharmazie 303 (11), 905- 12 (November 1970).

ELBERT L. ROBERTS, Primary Examiner D. G. RIVERS, Assistant Examiner s. (:1. X.R. 260-488 B, 489, 586 H; 424-312, 311, 331

UNITED SlAlES PATENT ()FFICE CERTlFlCATE OF CORRECTION Patent No. 3 g 810 9 7 Dated May 1 4 197 4 Inventor(s) John S. Bar'an and ChiDean Liang It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 16, "(lower alkenol)" should be (lower alkanoyl) Column 6, second formula,

" w should be CH CH 7 CH3 CH Column 7, lineY, "3B acecoxy" should be 38-acetoxy Signed and sealed this 8th day of October 1974.

(SEAL) Attest:

MCCOY M. GIBSON JR. C. MARSHALL DANN Attestlng Officer Conunissioner of Patents 3 FORM 1 0-2050 {10-69) USCOMMDC 6o376 p69 a U5. GOVERNMENT PRINTING OFFICE: I969 o-Jss-su 

